Manufacture of vitamin a



Patented Feb. 25, 1941 UNITED STATES.

PATENT OFFICE, I

MANUFACTURE OF VITANHN A Richard Kuhn, Heidelberg, Germany, and Colin J. 0. R. Morris, 'London, England, assignors to Winthrop Chemical Company, 1110., New York, N. Y., a corporation of New York No Drawing. Application March as. 1938, Serial No. 197,613. In Germany March 27, 1937 7 Claims.

In accordance with the present invention it is possible to obtain the vitamin A and its homologues synthetically. The process of manufacm ture of the invention consists in condensing pionylidene-acetaldehyde (compare copending application of even date) in the presencev of salts of secondary amines with crotonaldehyde or its higher homologues to -(p-ionylidene)-sorbinal- 15 dehyde or its homologues and reducing the aidehyde group in the aldehyde compounds obtained 7 in this manner to the alcohol group by means of mild reducing agents, for instance according to the methods of Meerwein and Ponndori, while retaining the double bond. Salts of secondary amines which are particularly suitable for the condensation are'the salts oi piperidine, for instance'piperidine acetate. For the reduction particularly aluminium alcoholates, especiaJly the '25 aluminates or secondary alcohols, such as isopropyl alcohol, have'proved suitable; when pmeithylcrptonaldehyde is used in the condensation a compound is obtained on reducing the condensation product, which corresponds in all its proper- 30 ties with the vitamin 4 obtained from natural substances. The reaction performs in this case according to the iollowing reaction scheme: H3O CH;

as BIC C-CH=CH-C=CHCHO nic-cwH-cno H; CH: Ha Ha fi p-lonylideno-acetaldehyda nic CH 5 mo C-CH=CH-C=OHOH=CHC=CH-CHO E: CH: H3 H;

Hi0 CHI c to mo c-cn=cn-c=cn-cn=cn-c=cn-cmon H: 4331 Hi Hi,

55 VitaminA It is advisable to perform the process in the absence or oxygen.

The invention is illustrated by the following example without-being limited thereto:

Example 3.9 grams of p-ionylidene-acetaldehyde are added to a mixture of 0.05 gram of piperidlne, 0.05 gram of glacial acetic acid and 0.05 cc. of alcohol. In an atmosphere of purenitrogen 1.5 gram of 10 p-methylcrotonaldehyde are added drop by drop during one hour. The reaction mixture assumes a dark brown coloration. After standing for several hours at ordinary temperature the mixture is diluted with ether, the piperidine washed out with very dilute hydrochloric acid, the ethereal solution is then shaken with dilute sodium carbonate solution and water and dried in a nitrogen atmosphere over sodium sulphate. The solution yields a deep blue-green coloration with antimony trichloride in chloroform. The ethereal solution oi the live-times unsaturated aldehyde is evaporated in a nitrogen atmosphere and the residue dissolved in 55 cos. of isopropyl alcohol (freshly distilled over aluminium). At a bath temperature of 110 C. 2 grams of aluminium isopropylate are added in a nitrogen atmosphere. The temperature is then elevated to 120 C. so that the isopropyl alcohol distils oil. About cos. of isopropyl alcohol are added three times un- 30 til the distilled alcohol does not give an acetone reaction with para-nitrcphenylhydrazine in glacial acetic acid (after about A 01 an hour). The cooled reaction mixture is then diluted with petroleum etherdboiling at30-40 C.) and extracted with 2 normal phosphorus acid solution. The aqueous layer is further extractedtwice with petroleum ether. The combined petroleum ether solutions are repeatedly washed" with water and dried over sodium sulphate.--"'I'his solution yields with antimony trichloride" in chloroform a deep blue coloration (absorption band 606111 By chromatographic adsorption, it desired repeated, on aluminium oxide from benzine and elutriatlon with benzene-benzine whereby the vitamin in every case is present in the highest layer, a pure product is obtained which shows the same properties as the vitamin A obtained from natural substances. 1 'y of the synthetic product has proved to be highly efiicacious in daily administration to rats when tested in accordance with the usual standardization method.

We claim:

1. The process which comprises condensing p= ionylidene-acetaldehyde in the presence of a salt 2 mascara of a secondary amine with p-methyl-cmtonaldehyde to -(p-ionylidene) -p-methyl-sorblnaldehyde and reducing the aldehyde group of the latter compound to the alcohol group by means 8 of an eluminate of a. secondary alcohol.

2. The process which comprises condensing fiionylidene-aceteldehyde in the presence of piperidine acetate with fi-methyl-crotonaldehydeto e- (p-ionylidene) -B-methyl-sorbineldehyde and 10 reducing the aldehyde group of the letter com= pound to the alcohol group by means of an alumi-' hyde to the in the D group by means oi an aluminate of a. secondary alcohol.

5. The process which comprises condensing p 'ionylidene-ecetaldehyde in the presence of a salt of a secondary amine with p-methyl-crotonalde- 5 e- (p-lonylidene) -p-methyl-sorbinsldehyde and reducing the aldehyde group of the latter compound to the-alcohol group by means of aluminium isopropylate.

6. The process which comprise condensing 18- i0 ionylidene-ecetaldehyde in the presence of piperidine acetate with p-methyl-crotonsldehyde to @-(s-ionylidene) -p-methyl-sorbinsldehyde and reduc the aldehyde group of the letter compound to the elcohol group by means of aluminium l5 isopropylete.

7. The process-which coins condensing in J. :1 so of oxygen ,B-ionylidm-acetaldehyde of piperidine acetate with pmethybneldf-e to r-(fl-ionylidenel-p- 20' methyl-sorbinsld;.. and reducing the aldehyde group of the latter compound to the alcohol group by 23s.! oi aluminium isopropylate.

RICHARD KUHN. 25 COLIN J. O. R. MORRIS. 

